Risk assessment dermal absorption/toxicity

McKee R, Freeman J. 1993. Dermal carcinogenicity studies of petroleum-derived materials. In RGM Wang, JB Knaak, HI Maiback, eds.. Health Risk Assessment Dermal and Inhalation Exposure and Absorption of Toxicants CRC Press, Ann Arbor MI, 263-21 A. 

Blancato, J. N., and Bischoff, K. B. (1993). The application of pharmacokinetic models to predict target dose. In Health Risk Assessment Dermal Inhalation Exposure and Absorption [Pg.610]

Wester RC, Maibach HI (1993) Animal models for percutaneous absorption. In Wang RGM, Knaak JB, Maibach HI (eds) Health risk assessment dermal and inhalation exposure and absorption of toxicants. CRC, Boca Raton, EL... 

Generally, the main pathways of exposure considered in tliis step are atmospheric surface and groundwater transport, ingestion of toxic materials that luu c passed tlu-ough the aquatic and tcncstrial food chain, and dermal absorption. Once an exposure assessment determines the quantity of a chemical with which human populations nniy come in contact, the information can be combined with toxicity data (from the hazard identification process) to estimate potential health risks." The primary purpose of an exposure assessment is to... 

A case can often be made to omit studies as scientifically unnecessary, because it is possible to conduct an adequate risk assessment without them. This is most often the case if the substance decomposes to degradants of known hazardous properties. For example the substance may hydrolyse rapidly to non-toxic products, so the key issue is to establish that this happens rapidly in the stomach before the parent substance can be absorbed. There may then be a case for omitting the expensive long-term animal studies, providing it is also established that there is no dermal or inhalation absorption from these exposure routes. In a similar way, it may be justified to omit ecotoxicity studies on a substance which hydrolyses or otherwise decomposes in the aquatic environment to stable products that have already been tested. 

Risk assessment and epidemiology could be successfully combined to analyze environmental health risks. Exposure assessments estimate concentrations of toxic chemicals in the environment that could be transferred to humans by ingestion, inhalation, or dermal absorption. In the future, there will be a greater need for agreement on how best to simultaneously assess societal risks involved with damage to both ecosystems and the human population (Ruttenber, 1993). 

Information on toxic effects of acute-duration exposure to PBBs by routes other than oral are limited to data on hepatic, renal, dermal, and ocular effects of inhalation and dermal exposure in rats or rabbits (Millischer et al. 1980 Needham et al. 1982 Norris et al. 1975a Waritz et al. 1977), but these data may not be reliable due to study limitations and possible delayed lethality. Quantitative data for inhalation and dermal absorption of PBBs are lacking. Studies of inhalation and dermal absorption following exposure to soil containing PBBs (i.e., bioavailability studies) would be useful for assessing risk at a hazardous waste... 

Walsh, C.T. 1990. Anatomical, Physiological, Biochemical Characteristics of the Gastrointestinal Tract. Iln T.R. Gerrity and C.J. Henry, Eds., Principles of Route-to-Route Extrapolation for Risk Assessment, pp 33-50. Elsevier New York, N.Y.Wester, R.C., and H.I. Maibach. 1997. Toxicokinetics Dermal Exposure and Absorption of Toxicants. In I.G. Sipes, C.A. McQueen, and A.J. Gandolfi, Eds., Comprehensive Toxicology Volume General Principles (J. Bond, volume editor), pp. 99-114. Pergamon Press, New York, N.Y. 

Because human pharmacokinetic data are often minimal, absorption data from studies of experimental animals-by any relevant route of exposure-might assist those who must apply animal toxicity data to risk assessment. Results of a dermal developmental toxicity study that shows no adverse developmental effects are potentially misleading if uptake through the skin is not documented. Such a study would be insufficient for risk assessment, especially if it were interpreted as a negative study (one that showed no adverse effect). In studies where developmental toxicity is detected, regardless of the route of exposure, skin absorption data can be used to establish the internal dose in the pregnant animal for risk extrapolation to human dermal exposure. For a discussion pertinent both to the development and to the application of pharmacokinetic data, risk assessors can consult the conclusions of the Workshop on the Acceptability and Interpretation of Dermal Developmental Toxicity Studies (Kimmel and Francis 1990). 

In the risk assessment, some steps are not well described. For example, subchronic toxicity studies and not chronic toxicity studies are used in the risk assessment. Exposure duration and frequency considerations are not discussed. Route-to-route extrapolation is considered acceptable implicitly, without further evaluation of the various issues involved. The rationale for using a dermal absorption default of 10 %, in the absence of data is also not discussed. 

This model has a straightforward structure and is simple to use. It is based on studies carried out in part for the specific purpose of model development. However, not all of the required information is publicly available. The databases are not described at the study level the exposure data are only available in classes, although more detailed information is available on request. The choice of the statistics is not discussed. In the risk-assessment approach, some steps are not clearly presented. Sub-chronic toxicity studies, and not chronic toxicity studies, are used in the risk assessment. Exposure duration and frequency considerations are not discussed. Route-to-route extrapolation is considered acceptable implicitly, without further evaluation of the various issues involved. The rationale for using a dermal absorption default of 10 %, in the absence of data, is not discussed. 

The present OECD and USEPA protocols typically focus on dermal uptake expressed as percentage of dose. In general, no information is provided on the rate of absorption (peak profile or sustained presence) and the metabolites formed, although some guidance on these issues exists (USEPA, 1998). This additional information on the behavior of the test substance could be very useful in (refinement oO the risk assessment. For instance, information on the metabolites formed after dermal exposure could be very helpful in addressing the question as to what extent oral toxicity studies could be used to assess the risk of the dermally exposed population. Information on the rate of absorption could be employed in a similar manner. This latter value can easily be obtained from in vitro smdies. 

In order to assess risk to individuals following dermal exposure to a pesticide, dermal absorption data are often required to convert dermal deposition data to estimates of systemic exposure. These estimates of systemic exposure are then compared with the No Observed Adverse Effect Levels (NOAELs) from oral toxicity studies or limit values (for instance. Acceptable Operator Exposure Levels (AOELs)) derived from these oral data (Bos et at., 1998 Rennen et al 1999). As noted in the introduction, oral studies are generally used because the toxicology database is typically focused on the oral route of exposure. 

Although this method of using the oral toxicity data for risk assessment of dermal exposed populations ( route-to-route extrapolation) appears straightforward, it may not be always applicable. If, for instance, fundamental differences in metabolism exist between the oral and dermal routes, excessive first-pass effects occur and/or large differences in rate of absorption exist between the various routes of exposure, route-to-route extrapolation may not be feasible (Pepelko and Withey, 1985 Sharrat, 1988). When there is uncertainty about the relevance of route-to-route extrapolation, oral and dermal kinetic data may be useful, or conduction of pivotal toxicological studies (e.g. development, neurotoxicology, etc.) by the dermal route may be the most appropriate way forward. 

Local skin effects are not the only consideration for dermal toxicity. The role of the skin as a barrier preventing the free penetration of exogenous chemicals into the systemic circulation is equally important. Indeed, it is becoming apparent that the dermal route of exposure is in many cases comparable to inhalation and oral absorption as a potential source of potentially toxic chemicals in the body and forms an integral part of many multi-media multi-pathway risk assessments. In this context, for example, the (US) National Institute of Occupational Safety and Health is currently revising its current skin notations (which identify chemicals likely to present dermal hazards in the workplace) to take into account a... 

Toxicity can occur secondary to exposure to treated fields since many of these compounds may be easily absorbed across the skin. The potential for dermal absorption is compound dependent and varies from 2-70% of the applied dose. These compounds may also be metabolized while being absorbed across the skin, and the environmental conditions during exposure (temperature, relative humidity) drastically modify absorption. Similarly, solvent effects and coapplication of other pesticides may modify the amount absorbed, making risk assessment from single-chemical data difficult. This is a primary reason that occupational exposure, and not food residues, should be the primary focus of pesticide toxicology. 

Purpose The dermal absorption data enable EPA to make risk assessments when the oral or inhalation route determined the toxic effects in defined faboratory animal models yet the exposure to humans is expected by the dermal route. A complete kinetic analysis is essential to convert oral or inhalation low-effect and no-effect doses into dermal low-effect and no-effect doses. This affows for the calculation of margin of exposure or risk to predict systemic toxic effects that otherwise may not be tested practicalfy by the dermaf route. The rat is the preferred model because a large toxicology database exists in this species. The rat absorption... 

Gettings, S.D., Howes, D., and Walters, K.A. (1998). Experimental design considerations and use of in vitro skin penetration data in cosmetic risk assessment, in M.S. Roberts and K. A. Walters (eds.). Dermal Absorption and Toxicity Assessment, New York Dekker, pp. 459-487. 

A second aspect of risk assessment for fragranced products concans systemic levels achieved by a combination of dermal absorption and inhalation. The hazards associated with each ingredient are earefuUy evaluated and eontroUed by a combination of exposure assessment plus intrinsic toxicity assessment (Gerberick and Robinson, 2000). Because most absorption occurs via the dermal route (caused by high dilution of the vapor into room air), skin absorption provides the link between these two areas. Absorption models should therefore attempt to answer the questions. What fraction of a topically applied dose will be absorbed and How rapidly will this occur ... 

The objective of the work described here was to examine whether a similar approach can be used to assess chemical uptake into the skin in vivo from contaminated soil. It is now well recognized that human skin contact with contaminated soil can represent an important route of exposure to toxic compounds in occupational, environmental, and recreational settings. Data on the dermal uptake of chemicals from soil, especially in vivo, are limited, however, and those that do exist may underrepresent the true risk. This is because the amount of soil applied to skin in these experiments (1) greatly exceeds the mass of soil adhering to skin during a typical exposure (U.S. Environmental Protection Agency, 2001) and (2) may have provided multiple soil layers that do not contribute equally to dermal absorption (Bunge and Parks, 1998). 

Drug and chemical dermal absorption typically involves experiments conducted using single chemicals, making the mechanisms of absorption of individual chemicals extensively studied (the subject of most chapters in this volume). Similarly, most risk assessment profiles and mathematical models are based on the behavior of single chemicals. A primary route of occupational and environmental exposure to toxic chemicals is through the skin however, such exposures are often to complex chemical mixtures. In fact, the effects of coadministered chemicals on the rate and extent of absorption of a topically applied systemic toxicant may determine whether... 

Nontechnical Summary In this paper, the process of risk assessment with compounds which exhibit chronic but not acute toxicity is first reviewed. The remainder of the paper is spent on reviewing the procedure for quantifying absorption through the skin. The test animal used is the rhesus monkey since previously published work has shown this animal to yield data most similar to man. Data are presented on oryzalin for which dermal absorption was less than 2 percent of the applied dose. The problems and shortcomings of the procedure as well as its advantage (similarity to man) are also discussed. 

These exposure estimates are not sufficient of themselves to define the amount of chemical Inhaled, absorbed or Ingested by the worker. The dose received by the worker Is also dependent on Intake and absorption factors such as breathing rate and dermal absorption rate. All of these factors must be considered for comparison of the estimated dose to the toxicity data In a risk assessment. Although these factors are often chemical specific, the exposure value, as we have defined It, Is not. We are therefore limiting our proposal to Include only worker exposure values which are free of chemical specific biases. 

Recently some emphasis has been placed on obtaining exposure data on each Individual compound under consideration. These studies can be costly In both time and money. In some cases they are not even a major factor In the judgement of risk simply because the toxicity and/or dermal absorption values are very low. In other cases the uncertainty of using exposure estimates from small sample groups compromises the risk assessment. Addressing these problems requires some form of data management. 

Figure 11.6 illustrates a process to follow to assess a substance s absorption potential. The first step is to establish the types of individuals (i.e., workers, consumers, or general population) at greatest risk of exposure and the known or likely routes (dermal, inhalation, or oral) by which exposure will take place. The second step is to determine whether measured absorption data for the substance are available. Such data are often not available, but animal absorption data can be used as surrogates for human data in many cases. If no measured absorption data are available, toxicity data from studies involving humans or animals exposed to the substance may be useful. For example, if systemic toxic effects were noted in humans or animals following dermal (or oral or inhalation) exposure to a substance, especially at low doses, then obviously the substance is absorbed via this route. 

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